DE69531488T2 - MEDICINE-CONTAINING, ADHESIVE, ASSEMBLABLE, TRANSDERMAL DISPENSER - Google Patents

Abstract

A method for making a transdermal drug delivery device for heat sensitive and volatile drugs is disclosed. The device contains a drug-containing adhesive composite layer having an impermeable backing material laminated to the distal surface thereof and a proximal peelable impermeable backing material adapted for removal for administering a drug to the skin or mucosa laminated to the proximal surface thereof. The method comprising the steps of providing first and second adhesive laminates each comprising a drug permeable adhesive layer having laminated to one surface one of said backing materials and having the opposing surface exposed. The drug, in gelled form and optionally containing additives such as enhancers and preservatives, is extruded onto at least one exposed surface of the first or second adhesive laminate followed by laminating together the exposed surfaces of the first and second adhesive laminate such that the adhesive layers and gelled drug are combined to form the drug-containing adhesive composite layer having the distal and proximal surfaces covered by the respective backing materials. The adhesives used in making up the laminates may be the same or different provided the drug is compatible with the adhesive. The process is particularly adaptable to the formulation of nicotine-containing patches. Drug delivery devices made according to the disclosed method and a method of using these drug delivery devices are also described.

Description

Background of the Invention:

This invention relates generally Transdermal and transmucosal drug delivery (TDD) units. In particular, the invention relates to TDD units for dispensing heat sensitive or more fleeting Drugs in which the drug is gel on an adhesive layer is extruded, the surface of the adhesive layer on which the Gel has been extruded, followed by a second adhesive layer is laminated to a drug-containing adhesive composite Generating unit. Chemical booster to facilitate the Transport of the drug through the skin or mucous membrane and other additives can also mixed with the drug or in the composite. Accordingly, the invention includes a method of making TDD units using an extrusion step to make one to put gelled drug into a dried, adhesive layer, and drug delivery units using the method were manufactured. These procedures and units are particular to deliver nicotine to the body useful.

Cigarette smoking is a major risk factor for coronary artery disease and the cause of approximately 30% of all Cancer deaths. However, it is difficult to quit smoking and any therapy to stop Smoking must deal with the pharmacological and psychological dependence deal with cigarettes. Modest success is by separating the treatment of these two Factors have been achieved by satisfying the pharmacological Addicts with nicotine pills or chewing gum during psychological addiction independently was treated.

One of the most successful approaches is based on nicotine chewing gum, through which absorption through the Cheek achieved direct release of nicotine into the systemic circulation becomes. However, nicotine gum tastes bad and can cause mouth ulcers and cause heartburn and destroyed Dental auxiliaries. Furthermore, patient compliance for effectiveness crucial. Other problems with oral nicotine include upset stomach, nausea, rapid nicotine breakdown and irregular and unpredictable blood levels on.

Another approach that is becoming increasingly popular for treating the pharmacological addiction to cigarette smoking is the transdermal delivery of nicotine. The skin is usually a very effective barrier to the passage of environmental materials into the body. However, nicotine is very volatile, very lipid-soluble, and easily penetrates the skin. For example, a comparison of the mean penetration rates of other transdermally administered agents through the skin shows that nitroglycerin has a skin flow value of 10-25 μg / cm ² · h, scopolamine of 2-8 μg / cm ² · h, estradiol of 0.01-0 , 03 μg / cm ² · h, clonidine of 0.5 μg / cm ² · h and nicotine of 100–300 μg / cm ² · h. However, nicotine is also very irritating to the skin and is very toxic. Therefore, the development of compatible TDD nicotine delivery devices requires that ways be found to minimize skin irritation and safety issues while delivering effective doses of the substance.

Several TDD nicotine delivery devices have been described. Japanese Patent Laid-Open No. 61-251619 reports an unregulated release unit that contains small amounts of the substance and covers a relatively large area (70 cm ² ) of the skin. U.S. Patent No. 4,597,961 to Etscorn discloses a unit in which a microporous membrane minimally regulates nicotine release to the skin so that it is only effective for about 45 minutes. U.S. Patent Nos. 4,920,989 and 5,016,652 to Rose et al. describes a nicotine patch that is preferably used with a nicotine aerosol spray that is delivered into a patient's mouth. In U.S. Patent No. 4,943,435 to Baker et al. A 12-24 hour period of a nicotine delivery transdermal patch is reported which includes a nicotine reservoir and a rate regulating polymer matrix to regulate nicotine diffusion through the skin. In U.S. Patent No. 4,908,213 to Govil et al. discloses a transdermal nicotine patch containing an antipruritant to counteract severe itching that may occur with transdermal nicotine administration. U.S. Patent No. 4,877,618 to Reed teaches a transdermal nicotine patch which contains a stack of alternating layers of adhesive and interlaminar to provide a relatively constant rate of diffusion through the skin over an extended period of time.

Method of manufacturing TDD units have not received much attention in the patent literature. In U.S. Patent No. 4,943,435 to Baker et al. is a procedure for Manufacture of a nicotine patch is disclosed, the nicotine being preferred is dissolved in an inert polymer matrix that the speed of the Nicotine release regulated. The weight percentage nicotine can according to the desired Loading in the monolithic matrix layer can be varied, however the polymer is over about 50 weight percent (wt%) nicotine after pouring does not really firm, keeping it in gel or liquid form. consequently is this process for making nicotine patches on polymers and nicotine loads that are limited polymerize correctly when mixed.

Another problem with polymers and fleeting Drug-containing drug delivery units in allowing the polymer-drug combination to dry must, even if the polymerization is in the presence of the drug is achieved. This is a problem for volatile drugs like nicotine, because the concentration of the volatile Drug during drying decreases, especially when the polymer is in an oven heated to accelerate drying. It would therefore be advantageous Avoid manufacturing processes that involve heating or drying after addition of a fleeting one Require drug to polymer.

Baker also teaches that many of the ordinary Materials from which components of the TDD units are made like porters, Adhesives, membranes, matrices and separating layers, dissolved by nicotine or be dismantled. For example, Baker teaches that adhesives get tough, lose their stickiness or become so heavily loaded with nicotine, that they're a very big one Push nicotine release when applied to the skin. According to Baker behave typical qualities of polyisobutylene, acrylate or of silicone-based adhesives this way if they use nicotine for periods of up to a week were exposed. Baker also teaches that in the presence of nicotine Significantly swelling, decomposing or completely dissolving polymers many qualities of polyvinyl chloride, polycarbonate, polystyrene, polyethylene terephthalate, Polybutyrate, polyurethane, ethylene-vinyl acetate copolymers (except those with low percentages of vinyl acetate) and polyvinylidene chloride.

In U.S. Patent No. 4,915,950 to Miranda et al. describes a method for manufacturing TDD units, which is the lamination of a mounting adhesive layer onto one impermeable drug carrier includes. More like that An adhesive contact adhesive is laminated onto a release liner. Then an adsorbent swelling layer is preferably applied to the Contact adhesive or the fastening adhesive applied. On Drug in liquid Mold is then printed on the exposed surface of the adsorbent swell layer. Finally the fastening adhesive / carrier laminate onto the swelling / contact adhesive / separating layer laminate laminated to create the finished unit. The printing step includes the application of the liquid drug on the adsorbent source layer on a substantially constant manner by one of several methods. The Use of a drug in liquid form poses a significant problem because the drug wets the surface of the swelling layer needs so pressing the liquid while lamination to the periphery of the unit is substantially prevented becomes. After application, the drug diffuses into one or both of the adjacent adhesive Layers. Hence must the tissue material forming the swelling layer and its surface properties so carefully selected be that the suction into the tissue is carefully regulated. The speed, with which the liquid Drug is printed on the swelling layer, and the subsequent one Lamination on the adhesive laminate must therefore also be carefully regulated become. It is difficult.

In U.S. Patent No. 5,110,599 to Anhauser also a method of making transdermal patches discloses a printing process.

Tasks and summary the invention:

An object of the present invention is a method of manufacturing laminated TDD units provide that with volatile or heat sensitive Drugs, enhancers or other components that cannot be dried or heated, for example in an oven.

Another object of the invention is a method of manufacturing laminated TDD units to provide, wherein sorption or suction of a liquid drug formulation into a sorbent layer is not required.

Another object of the invention is a method of manufacturing laminated TDD units to provide the selection and optimization of drug delivery profiles allows.

• (a) Bereitstellen eines ersten adhäsiven Laminats, umfassend eine erste Arzneistoff-durchlässige adhäsive Schicht, auf deren eine Oberfläche ein distales Trägermaterial laminiert ist und deren gegenüber liegende Oberfläche exponiert ist,
• (b) Bereitstellen eines zweiten adhäsiven Laminats, umfassend eine zweite adhäsive Schicht, auf deren eine Oberfläche eine proximale abziehbare Folie laminiert ist und deren gegenüber liegende Oberfläche exponiert ist,
• (c) Extrudieren des Arzneistoffs in Gelform auf mindestens eine exponierte Oberfläche des ersten oder zweiten adhäsiven Laminats und
• (d) Zusammenlaminieren der exponierten Oberflächen des ersten adhäsiven Laminats und des zweiten adhäsiven Laminats, so dass die adhäsiven Schichten und der gelierte Arzneistoff so kombiniert sind, dass sie die Arzneistoff-enthaltende, adhäsive, zusammengesetzte Schicht erzeugen, wobei das distale Trägermaterial deren eine Oberfläche bedeckt und wobei die proximale abziehbare Trennlage deren gegenüber liegende Oberfläche bedeckt.

These and other tasks can be accomplished by a method of manufacturing a TDD unit that includes the following steps:

• (a) providing a first adhesive laminate comprising a first drug-permeable adhesive layer, on one surface of which a distal carrier material is laminated and on the opposite surface of which is exposed,
• (b) providing a second adhesive laminate comprising a second adhesive layer, on one surface of which a proximal peelable film is laminated and on the opposite surface of which is exposed,
• (c) extruding the drug in gel form onto at least one exposed surface of the first or second adhesive laminate and
• (d) laminating the exposed surfaces of the first adhesive laminate and the second adhesive laminate together so that the adhesive layers and the gelled drug are combined to produce the drug-containing adhesive composite layer, with the distal carrier material whose one surface is covered and the proximal removable separating layer covers its opposite surface.

In other words, the drug in gel form, which may contain enhancers, preservatives, antioxidants, Contains anti-irritants, solubilizers and the like on one or both of the exposed surfaces of the first or second adhesive Layer are extruded, which are then laminated together, a drug-containing adhesive composite layer to create.

Another aspect of the process is the protection of the exposed surfaces of both the first and also the second adhesive Shift during the manufacture of the unit with process separation layers prior to extrusion the gelled drug onto an adhesive surface and prior to lamination of the exposed surfaces of the two adhesive Layers are removed to make the drug / adhesive composite to create. In this embodiment the extrusion of the gelled drug, followed by the lamination, on every adhesive Shift performed become. Moreover could extrusion of the gelled drug, if desired, also on both adhesive Shifts performed become.

Another point of view and an even more special embodiment The method consists of using TDD units for the administration of Nicotine for a therapy to stop of smoking. Gelled nicotine is mixed formulated with a gelling agent such as hydroxypropyl cellulose. A preservative or an antioxidant such as butylated Hydroxytoluene can also be added to the formulation.

Brief description of the Drawings:

1 shows a partially schematic sectional view of a TDD unit according to the present invention.

2 FIG. 12 shows a partially schematic sectional view of a laminated first adhesive intermediate used in manufacturing the TDD unit of FIG 1 is used.

3 FIG. 12 shows a partially schematic sectional view of a laminated second adhesive intermediate used in manufacturing the TDD unit of FIG 1 is used.

4 shows a partially schematic sectional view of a complete TDD unit according to 1 with an additional overlapping proximal divider flap.

Detailed description of the invention:

Before the present procedure for Manufacture of transdermal and transmucosal drug delivery units disclosed and described is to be taken for granted that this invention is not limited to the specific disclosed herein Process steps and materials is limited because of such process steps and materials change a little can. It also goes without saying that the one used here Terminology only for the purpose of describing certain embodiments is used and not restrictive because the scope of the present invention is only through the attached ones claims limited is.

It has to be stated that the singular forms " one, one "and" the, the, the "as in this description and the attached claims used, include plural equivalents, as far as the content is not undoubtedly pretends otherwise. Hence, for example, closes the reference to a laminated structure containing "a drug", a mixture of two or includes more drugs, the Terms of "one Glue "the cover on two or more such adhesives and the reference to "an enhancer" includes the reference to Mix of two or more amplifiers on.

When describing and claiming The present invention uses the following terminology as defined used, which are set out below.

Here, the terms "active gel", "gelled drug", "drug in gel form" and the like mean a drug in which a gelling agent is dispersed to obtain selected flow and surface tension properties for application to laminated plasters. Thus, an active gel is a liquid drug in a viscous but flowable state and can be a colloidal / biphasic or dissolved mixture of the liquid drug and a gelling agent. A liquid drug means either a drug which is itself a liquid or which is dissolved, suspended or dispersed in a selected solvent or carrier. Such a solvent could be a liquid such as ethanol, water and the like or a low viscosity semi-solid that can be extruded such as low molecular weight polymers, waxes, petroleum jelly and the like. An active gel can also include enhancers that can be added to the formulation to facilitate the transport of the drug through the skin or mucosa into the body. An active gel can also be a Kombina tion of drugs, gelling agents, enhancers, preservatives, antioxidants, anti-irritants, solubilizers and the like. The term "gel" is intended to be applied to the functional nature of the thickened drug component regardless of whether the technical definition of a gel is met or not.

Here, the terms "drug" or "pharmacological agent" or other similar term mean any chemical or biological material or compound that is suitable for transdermal or transmucosal administration by methods previously known in the art and / or by the present invention are suitable methods which induce a desired biological or pharmacological effect, which may include, but are not limited to, (1) influencing life processes, (2) a prophylactic effect on the organism and the prevention of an undesirable biological effect, such as the Preventing infection, (3) alleviating a condition caused by a disease, for example alleviating pain or inflammation caused as a result of an illness, and / or (4) either alleviating, reducing or completely eliminating it the disease from the organism. The effect can be local, such as providing local anesthetic, or it can be systemic. This invention does not relate to new drugs or new classes of drugs. Rather, it is limited to devices and methods of making the drug delivery devices or agents that exist in the art or that can later be manufactured as active drugs or agents that are suitable for delivery according to the present invention. Such substances include broad classes of compounds that are normally released into the body, including through body surfaces and membranes, including skin and mucous membranes. Generally this includes but is not limited to:
Anti-infectives such as antibiotics and antivirals; Analgesics and combinations of analgesics; anorexics; anthelmintic; antiarthritic; Antiasthmatic agents; anticonvulsants; antidepressants; antidiabetics; antidiarrheals; Antihistamines; anti-inflammatory drugs; Antimigraine preparations; Antinauseants; Antineoplasie means; Anti-Parkinsonian drugs; Antijuckmittel; antipsychotics; antipyretics; antispasmodics; anticholinergics; sympathomimetic; Xanthine derivatives; Circulatory preparations including potassium and calcium channel blockers, beta blockers, alpha blockers and antiarrhythmics; antihypertensives; Diuretics and antidiuretics; Vasodilators, including generally coronary, peripheral and cerebral; Central nervous system stimulants; vasoconstrictors; Cough and cold preparations, including constipation relievers; Hormones such as estradiol and other steroids, including corticosteroids; Sleeping pills; Immunsup pressiva; muscle relaxants; parasympatholytics; Psychostimulants; sedatives; Tranquillizers and nicotine and their acid addition salts.

The flow of a drug through The skin or mucous membrane can be changed by either resistance (the diffusion coefficient) or the driving force (the diffusion gradient) elevated become. More like that The flow of an analyte (chemical or biological Material that is suitable for passage through a biological membrane which is an individual's concentration or activity within of the body want to know), through the skin or mucous membrane for collection or analysis the outside of the body also increased become. The flow can be reduced by using so-called intrusion or chemical amplifiers elevated become. Chemical boosters include two main classes of components, i. H. Cell envelope interfering connections and solvents or binary Systems that have both cell envelope interfering connections as well as solvents contain.

Cell envelope interfering compounds are known in the art as useful topical pharmaceutical preparations and are also effective in weaning analytes through the skin. These compounds are believed to assist in skin penetration by disrupting the lipid structure of the stratum corneum cell shells. A comprehensive list of these compounds is described in European patent application 0 043 738, published June 13, 1982. Any cell envelope interfering compound is believed to be useful for the purposes of this invention. Examples of the cell envelope interfering compounds are those which are represented by the following formula: RX wherein R is a straight chain alkyl group with about 7 to 16 carbon atoms, a non-terminal alkenyl group with about 7 to 22 carbon atoms or a branched chain alkyl group with about 13 to 22 carbon atoms, and X is sorbitan, glycerin, -ON, -COOCH ₃ , -COOC ₂ H ₅ , -OCOCH ₃ , -SOCH ₃ , -P (CH ₃ ) ₂ O, -COOC ₂ H ₄ OC ₂ H ₄ OH, -COOCH (CHOH) ₄ CH ₂ OH, -COOCN ₂ CHOHCH ₃ , -COOCH ₂ CH (OR '') CH ₂ OR '', - (OCH ₂ CH ₂ ) _m OH-, -COOR 'or -CONR' ₂ , where R 'is -H, -CH ₃ , -C ₂ H ₅ , -C ₃ H ₇ or C ₂ H ₄ OH; R '' represents -H or a non-terminal alkenyl radical with about 7 to 22 carbon atoms; and m is 2-6; with the proviso that when R '' is an alkenyl radical and X is -OH or -COOH, there is at least one double bond in the cis configuration. Preferred cell envelope interfering compounds include isopropyl myristate, methyl laurate, oleic acid, oleyl alcohol, glycerol monooleate, glycerol dioleate, glycerol trioleate, glycerol monostearate, glycerol monolaurate, propylene glycol monolaurate and sorbitan esters and mixtures thereof.

Suitable solvents include water; Diols such as propylene glycol and glycerin; Monoalcohols, such as ethanol, Propanol and higher alcohols; DMSO; dimethylformamide; N, N-dimethylacetamide; 2-pyrrolidone; N- (2-hydroxyethyl) pyrrolidone, N-methylpyrrolidone, 1-dodecylazacycloheptan-2-one and other N-substituted alkylazacycloalkyl-2-ones (Azone) and the like.

U.S. Patent No. 4,537,776, Cooper, issued on August 27, 1985 an excellent summary of the state of the art and background information, which describes in detail the use of certain binary systems for penetration enhancement.

The European patent application teaches in a similar way 0 043 738, which relates to the foregoing, the use selected Diols as solvents along with a wide class of cell envelope interfering delivery compounds of lipophilic pharmacologically active compounds.

A binary system for enhancing metoclopramide penetration is disclosed in UK Patent Application GB 2,153,223 A, published August 21, 1985, and consists of a monohydric alcohol ester of a C _8-32 aliphatic monocarboxylic acid (unsaturated and / or branched when C _18-32 ) or a C _6-24 aliphatic monoalcohol (unsaturated and / or branched when C _14-24 ) and an N-cyclic compound such as 2-pyrrolidone, N-methylpyrrolidone and the like.

Combinations of diethylene glycol monoethyl or monomethyl ether enhancers with propylene glycol monolaurate and methyl laurate are disclosed in U.S. Patent No. 4,973,468 because they increase transdermal delivery of steroids such as progesterones and estrogens. A dual amplifier consisting of glycerol monolaurate and ethanol for transdermal delivery of drugs is shown in U.S. Patent No. 4,820,720. In U.S. Patent No. 5,006,342, numerous transdermal drug delivery enhancers are listed that consist of fatty acid esters or fatty alcohol ethers of C ₂ to C ₄ alkanediols, with each fatty acid / alcohol portion of the ester / ether being about 8 to 22 carbon atoms , U.S. Patent No. 4,863,970 shows penetration-enhancing compositions for topical use which are an active penetrant contained in an intrusion-enhancing carrier containing certain amounts of one or more cell envelope interfering compounds such as oleic acid, oleyl alcohol and glycerol esters oleic acid; a C ₂ or C ₄ alkanol and an inert diluent such as water.

Other chemical enhancers that not necessarily associated with the binary systems included DMSO or aqueous solutions by DMSO as described in Herschler, U.S. Patent No. 3,551,554; Herschler, U.S. patent No. 3,711,602; and Herschler, U.S. Patent No. 3,711,606, and the azones (N-substituted alkyl azacycloalkyl-2-ones) as described by Cooper found U.S. Patent No. 4,557,943.

Some chemical amplification systems can have negative side effects such as toxicity and skin irritation. In U.S. Patent No. 4,855,298 are compositions for reducing of skin irritation revealed by chemical enhancers Compositions with skin irritant properties with a lot of glycerin that is sufficient to have an anti-irritating effect to enable. consequently can Anti-irritant beneficial to drug / enhancer compositions be added within the scope of the invention.

The solubility of certain drugs in some adhesives used in the adhesive laminates described here used can be disadvantageously low. solubility reinforcing Means, solution aids or solubility changing Means can added to drug formulation to increase drug solubility and consequently the drug concentration in the adhesive laminates to improve. The increase the drug concentration in the adhesive laminates also increases the transdermal or transmucosal flow. Examples of such solubilizing agents conclude Solvent, such as short-chain alcohols, diols and triols, polymers with a lower Molecular weight, such as polyethylene glycol and polypropylene glycol, and other substances that increase of solubility of the drug in the adhesive Layers are suitable.

The in the 1 - 4 Embodiments described are presented with respect to nicotine as an active drug. However, those skilled in the art will recognize that any other liquid drug contained in an active gel that can be delivered transdermally or transmucosal can be used in place of nicotine. It is to be emphasized that the present invention is specially designed for the formulation of drugs, enhancers or other constituents of the formulation which are volatile or sensitive to heat and which cannot be easily formulated under conditions in which elevated temperatures are required. Because the terms "volatile" or "heat sensitive" can be considered relative, drugs, enhancers, or other components of the formulation are considered herein to be "volatile" or "heat sensitive" for purposes of definition if they have a melting point, decompose, or sub about 100 ° C, especially below about 75 ° C and especially below about 50 ° C.

In 1 the TDD unit provided by the present method is commonly used 10 shown. The unit 10 is in the form of a laminated drug-containing adhesive composite layer which is designed to adhere to a predetermined area of the intact skin or mucosal tissue. The individual layers of the unit 10 essentially have one Drug-impermeable distal carrier 14 , a drug-laden adhesive composite layer 18 , which is designed in such a way that it sticks to the skin or mucous membrane, and an essentially drug-impermeable proximal separating layer 22 on. The adhesive, compound layer 18 has a distal adhesive layer 19 , a proximal adhesive layer 20 and a gelled drug layer therebetween 21 on. These layers are described in more detail below.

The distal support layer 14 defines the side of the patch facing the environment when used, ie distal to the skin or mucous membrane. The functions of the backing layer 14 is to protect the patch and provide an impervious layer that prevents loss of nicotine (or other liquid or volatile drugs) to the environment. As a result, the material selected should be nicotine resistant and minimal permeable to nicotine. The carrier material can advantageously be opaque in order to protect the nicotine from degradation when exposed to UV light. Furthermore, the backing layer should 14 be able to bind to and support the other layers of the unit, but should be flexible to adapt to the movements of a person who is the unit 10 used. A preferred material is polyester or aluminized polyester, for example polyester medical film such as that marketed by 3M Corporation under the trade name Scotchpak ^® 1009 or 1109th Aluminized polyester has a nicotine permeability of less than about 0.2 μg · 100 μm / cm ² · h. There are a limited number of materials that are sufficiently impervious to nicotine to adequately retain nicotine loading during storage or use. However, other usable materials with low permeability with or without modifications are those selected from the group consisting of metal foils, metallized poly foils, composite foils or foils containing polyester, such as polyester terephthalate, polytetrafluoroethylene ("TEFLON ^® ") - Materials or equivalents thereto, polyether block amide copolymers (e.g. "PEBAX" copolymers), polyethylene-methyl methacrylate block copolymers, such as "NUKRELL ^TM " polymers, polyurethanes, such as "PELLATHANE ^TM " or "ESTANE ^TM " polymers, polyvinylidene chloride ( Saran ^® ), nylon, silicone elastomers, rubber-based polyisobutylene, styrene, styrene-butadiene and styrene-isoprene copolymers, polyethylene and polypropylene.

Although many of these materials are in U.S. Patent No. 4,943,435 to Baker is unsuitable for use with Nicotine has been cited, it is believed that the materials listed sufficiently stable against nicotine breakdown are described in the present Invention useful to be when formulated in the manner described here become. A thickness of approximately 25 μm up to 100 μm is preferred, with 50 microns up to 75 μm stronger are preferred.

The adhesive (s) used to form the adhesive / drug composite 18 is / should be used, should be nicotine compatible and allow a useful nicotine flow. The proximal 20 and distal 19 Adhesive layers play in determining the rate at which the nicotine comes out of the unit 10 released, leading roles. The material that the proximal adhesive layer 20 is an adhesive skin contact adhesive that contains a pharmaceutically acceptable material. It should also meet the general criteria for adhesives used for transdermal patches, including biocompatibility, ease of use, and ease of removal. The adhesives in both the proximal 20 as well as the distal 19 adhesive layer are preferably made of materials in which nicotine has a moderate diffusivity. After equilibrium, the fabric is everywhere in the adhesive, compound layer 18 spread out what is useful for regulating the release kinetics. Consequently, the distribution of nicotine can be achieved through careful selection of materials used for the adhesive, composite layer 18 used to be regulated anywhere in the entire system. Other useful criteria include sufficient drug solubility in the adhesive layers to create storage. The adhesive, compound layer 18 preferably has a thickness in the range of about 25 microns to 50 microns, more preferably from 50 microns to 250 microns, and most preferably from 50 microns to 125 microns. Suitable adhesives for use in practicing the invention include acrylic adhesives such as those marketed under the trade names RA2484, RA2333, RA2397, R363 and R362 by Monsanto Co.; other acrylic adhesives such as DUROTAK ^® 80-1196 (National Starch, crosslinked or non-crosslinked acrylic copolymer), SP18305 ^™ (Avery International), MSX435 ^TM (3M) and "NEOCRYL ^TM" (Polyvinyl Chemicals, Ltd ..); Vinyl acetate adhesives such as Air Products' Flexcryl ^™ -1614, -1617, -1618, and -1625; and natural and synthetic rubbers including polyisobutylene, neoprene, polybutadiene and polyisoprene. Other suitable materials include ethylene vinyl acetate copolymers, polysiloxanes, polyacrylates, polyurethanes and plasticized mass of polyether block amide copolymers ("PEBAX" copolymers). As in the case of the carrier materials, some of these materials are described in U.S. Patent No. Baker's 4,943,435 reports that they are released, attacked or degraded by nicotine, but the results showed that they are suitable materials for making nicotine-containing delivery units when properly formulated according to the present invention.

The adhesives that make up the distal adhesive layer 19 and the proximal adhesive layer 20 may be the same or different. If they are different, the choice of adhesives can be used to control or regulate drug distribution within the adhesive composite layer 18 be used. For example, if the drug is in the glue that covers the distal layer 19 includes, is more soluble and penetrates easily than in the adhesive that the proximal layer 20 then the adhesive could be the proximal layer 20 with respect to the diffusion of the drug from the unit 10 out to the surface of the skin or mucous membrane. The thickness of the distal layer 19 and the proximal layer 20 can also be selected to set the desired values of storage capacity and control of diffusion. If the drug is in the proximal layer 20 is more soluble and penetrates more easily, then it is possible to rapidly release a selected amount of drug from the proximal layer 20 and prolonged release of a selected amount of drug from the distal layer 19 set over a selected period. Another possible arrangement is that either the distal layer 19 or the proximal layer 20 or both are a composite. If for example the proximal layer 20 a composite of a proximal intermediate layer in which the drug is very soluble and penetrates it more easily, and a distal intermediate layer in which the drug is less soluble and penetrates less easily, and the distal layer 19 consists of a polymer in which the drug is very soluble and penetrates it easily, the drug quickly from the proximal intermediate layer of the proximal layer 20 released, the release from the distal layer 19 by the speed-determining properties of the distal intermediate layer of the proximal layer 20 is regulated. Those skilled in the art will be able to devise other useful arrangements based on these basic rules.

The proximal separation layer 22 covers the skin-facing or proximal side of the TDD unit 10 until the unit 10 is used. That is why the proximal separating layer 22 have the same or similar properties as the carrier 14 , and the same materials are preferred. Immediately before using the unit, the proximal separating layer becomes 22 removed to the nicotine-containing adhesive composite layer 18 exposed for contact and adhesion to the skin or mucosal surface.

As stated in the following description, the drug-containing adhesive is 18 in fact, a composite made by bringing two adhesive layers together after applying nicotine in gel form to the surface of at least one of them. The adhesives that produce each layer can be the same or different, but must be compatible and capable of absorbing the nicotine, but must allow it to diffuse from the adhesive to the skin or mucous membrane at an acceptable flow rate.

Active gel:

Nicotine is a clear liquid with approximately the same viscosity as water. However, extrusion coating requires a viscous liquid, and viscosity affects coating speed and application accuracy. The viscosity is preferably in the range of about 1 to 20 kg / m · s (1,000 to 200,000 centipoise), more preferably in the range of about 1 to 50 kg / m · s (1,000 to 50,000 centipoise), and most preferably in the range of about 2 to 20 kg / ms (2,000 to 20,000 centipoise). In order to effectively extrude the nicotine onto an adhesive layer in a controllable manner, such as through an extrusion slot mold, the drug must be thickened to an acceptable viscosity. Hydroxypropyl cellulose ("HPC"), a water-soluble polymer available in pharmacopoeia quality, is a preferred gelling agent that can be added to nicotine to increase its viscosity. HPC complies with the requirements of the National Formula for Heavy Metal Levels. HPC becomes nicotine preferably in the range of about 1-5% (w / w), more preferably in the range of about 2-4% (w / w) and most preferably in the range of about 2.5-3.5% (f / w) added. A particularly preferred source of HPC is Aqualon (Wilmington, Delaware), which markets HPC under the trade name KLUCEL ^® . Other gelling agents can also be used to advantage, such as acrylic polymer thickeners [AMSCO 6038A ^™ (Unocal)], methyl cellulose, hydroxymethyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, low molecular weight polymers, petroleum jelly and the like.

Another characteristic of nicotine, that can be problematic is its tendency in the presence of light and easily oxidize air. To avoid oxidation during storage, the nicotine should be in a dark container and preferably in a dark closet. Flood the reservoir with an inert gas, such as nitrogen, also reduces oxidation. While The production of nicotine patches is done by adding oxidation an antioxidant to the active gel. A favorite The antioxidant is butylated hydroxytoluene (BHT). BHT will with nicotine preferably in the range of about 0.01-1.0% (w / w), stronger preferably in the range of about 0.03-0.3% (w / w) and most preferably mixed in the range of about 0.05-0.2% (w / w). Other suitable antioxidants include butylated hydroxyanisole (BHA), sodium metabisulfate, maleic acid, EDTA, cysteine hydrochloride and α-tocopherol on.

The active gel is made by adding HPC to nicotine with stirring, taking care to avoid clumping the gel. BHT is also added and mixed with stirring. Then it will be the mixture of nicotine, HPC and BHT tightly sealed in a container and mixed for an extended period of time to ensure that the gelling agent is completely dissolved and that the mixture is homogeneous.

Example 1:

The active gel was obtained by combining 96.9% (w / w) nicotine in free base form, 3.0% (w / w) HPC (KLUCEL GF ^™ , an HPC form with a low molecular weight of approximately 370,000) and 0 , 1% (w / w) BHT produced at room temperature. These components were mixed on a roller mill for 26.5 hours and then the active gel was stored under a nitrogen atmosphere.

Adhesive primary intermediate laminate:

2 shows an adhesive primary intermediate laminate 26 which is used in the manufacturing process of 1 shown TDD unit 10 is used. This primary intermediate laminate 26 consists of an impermeable support 14 , an adhesive layer 19 and a process separation situation 30 , The carrier 14 is the same carrier 14 which creates the outer or distal cover of the TDD unit, as in 1 shown and has already been described. The adhesive 19 is in relation to the drug-loaded adhesive composite layer 18 the finished unit 10 of 1 has also been described and includes the distal adhesive layer 19 in the finished unit 10 , The thickness of the adhesive layer 19 in the adhesive primary intermediate product laminate 26 is only a part or part of the thickness of the loaded adhesive composite layer 18 ( 1 ) the unit 10 once it is manufactured as a TDD because of the adhesive layer 19 of the adhesive primary intermediate laminate 26 and the adhesive layer 20 of an adhesive secondary intermediate laminate 34 (described in relation to 3 ) are laminated together with the gelled drug to form the drug-containing adhesive composite layer 18 the unit 10 ( 1 ) to create. In the preferred manufacturing process, the process separation layer 30 during the manufacture of the primary intermediate 26 on the adhesive layer 19 laminated, but is part of the process of making the unit 10 removed again. However, in certain circumstances, e.g. B. if the adhesive layer 19 The process separation situation can be adequately protected 30 can be omitted from the TDD manufacturing process. The process separation situation 30 can be from any of the proximal separating layers 22 of 1 described materials exist. As currently described, the process separation comes 30 however, never in contact with nicotine, so it does not need to be made from a material that is resistant to nicotine degradation or penetration.

The adhesive primary intermediate laminate 26 can be made to order using any number of existing processes. One such method is slot die extrusion, in which a thin, uniform layer of a casting solution is extruded onto a carrier material. In a preferred embodiment of this method, the casting solution, a liquid formulation of an adhesive material in a suitable solvent, becomes an extrusion slot mold on a release liner at a controlled rate 30 pumped, creating a "coated web" with an exposed adhesive surface. Then the coated web or continuous roll of an adhesive-coated release liner is passed through a drying oven, with excess solvent from the adhesive coating or layer 19 be removed. The carrier film 14 is then applied to the exposed surface of the dried adhesive cast 19 on the separation layer 30 laminated, creating the primary laminate 26 is ended, which is then wound into a roll form. Optimal coating parameters can be determined regardless of the adhesive chosen. Fully adjustable range, pouring solution flow and drying parameters allow this process to be used in a variety of different types of adhesives. The adhesive does not contain any drug at this point in the process. An alternative to extruding the casting solution onto the release liner 30 is the extrusion of the casting solution onto the carrier film 14 ,

Example 2:

An adhesive primary intermediate laminate 26 was with an acrylic adhesive coating 19 manufactured. The acrylic adhesive (National Starch 80-1196) was dissolved in a solvent to produce a casting solution consisting of 45% adhesive, 8.25% ethyl acetate, 25.30% isopropyl alcohol, 2.75% toluene and 18.70% heptane duration. The casting solution was extrusion-molded onto a lightweight silicone-polyester release liner 30 (3EST-A-S242M release technologies) extruded on a two-zone coating / drying / laminating machine. The heating zones within the machine drying oven were 80 ° C and 100 ° C and the speed of the street was set at 6 feet per minute. The dried laminate, ie the adhesive 19 and the separation layer 30 , were then made with an aluminized, meat-colored Scotchpak ^® 1109- (3M) carrier film 14 covered and rewound for later use.

Adhesive secondary intermediate laminate:

In 3 it is shown that the secondary adhesive intermediate laminate 34 from an adhesive layer 20 is built between a process separation 30 and a proximal separation layer 22 is laminated. All of these components have been described above. The adhesive secondary intermediate laminate 34 is manufactured in a manner similar to that of the primary intermediate adhesive laminate 26 is similar. A casting solution of glue 20 is made by slot extrusion on a release liner 22 applied and then dried. Instead of laminating a carrier film as with the primary intermediate product, this then becomes a process separation layer 30 laminated to the adhesive release liner structure.

Manufacturing the active laminate:

The active laminate TDD 10 becomes from the active gel and the two intermediate laminates 26 and 34 , as described above. If available, the process separation layers 30 from each of the primary 26 and secondary intermediate laminates 34 deducted. The gelled drug is then applied to the adhesive layer of either the primary 26 or secondary intermediate laminates 34 extruded, and the laminates are pressed together to form the adhesive layers 19 and 20 and the gelled drug layer 21 to the adhesive, compound layer 18 connect to. In another embodiment, the gelled drug can enter the lamination interface between the adhesive layers 19 and 20 extruded when laminated together to form the adhesive, composite layer 18 to create. With any process, the result is an active laminate 10 ,

After the active laminate 10 patches are cut to the desired size and shape. An example of a suitable device for this purpose is a rotary punch, such as a standard Webtron 650 punch machine. The active laminate 10 can be cut into plasters of practically any size depending on the dosage conditions. The laminate 10 is threaded onto the punching machine, the separation layer 22 which is the adhesive, compound layer 18 covered, is subtracted. Instead of the separation layer 22 cover strips of release liner material are relaminated onto the adhesive surface. As in 4 shown, the cover strips overlap slightly to a small flap 36 for easy peeling of the separating layer in use. The cutout pattern is generally centered over the overlap of the deck divider strips, so the tab 36 is centered in the pavement. This type of release liner is considered equivalent to the release liner used in the initial manufacture because they both perform the same functions of protecting the adhesive layers of the TDD unit and retaining the drug within the unit. Accordingly, removal of one separator layer and replacement with another are within the scope of the invention. Therefore, the term "separating layer" and / or "peelable film" is intended to encompass any and all embodiments of protective layers and / or films. The resulting patches are then heat sealed in bags.

Example 3:

The active laminate 10 was from the two intermediates previously described 26 and 34 made using a coating / laminating machine. The adhesive secondary intermediate laminate 34 was led through the machine so that the process separation 30 was peeled off, with the distal surface of the adhesive layer 20 and the separation layer web 22 have been exposed. Active nicotine gel was extruded through a slit mold onto the adhesive layer 20 applied. Gelled drug was pumped to a slot shape with a Zenith gear pump (capacity 0.066 ml / revolution) and extruded onto the adhesive surface. The separation layer 30 of the adhesive primary intermediate laminate 26 was from the adhesive layer 19 peeled off and the remaining adhesive / carrier film ( 19 and 14 ) of the adhesive primary intermediate laminate 26 was applied to the active gel-coated adhesive layer 20 of the adhesive intermediate intermediate laminate 34 laminated to an adhesive, compound layer 18 to create. The adhesive weight of the composite laminate thus obtained was 16.2 mg / cm ² . The drug content of the active laminate was determined to be 1.98 mg nicotine per cm ² . This active laminate 10 was stored in a foil pouch and protected from light to minimize drug loss.

The active laminate 10 was converted into plasters and sealed in bags as soon as possible after the production of the active laminate. The separation layer 22 was made of active laminate 10 removed and was replaced by overlapping cover strips of release liner material, leaving tabs 36 for easy removal of the separating layer 22 were generated. Active 10 cm ² plasters were cut out of the active laminate using a rotary punching machine with standard mold equipment. The patches were checked after cutting and placed in polyethylene-lined aluminum foil bags heat sealed. Whole patches were checked and found to contain 1.96 mg nicotine / cm ² .

Example 4:

Nicotine patches were made by extruding nicotine gel directly into the lamination nip while simultaneously laminating the adhesive surfaces together 19 and 20 manufactured. The nicotine gel was prepared as described in Example 1 and extruded into the laminating interface using a syringe pump at 180 mg / min. The drug loading was varied by changing the speed of the lamination line from 1.6 to 4.0 feet / min. The nicotine-loaded adhesive laminates were then stored in foil-lined bags. Patches (10 cm ² ) were punched using a rotary die cutter and sealed in protective polyethylene-lined pouches as described above. The nicotine patches were tested for nicotine content and the results are shown in Table 1.

Example 5:

In vitro skin flow studies were performed using modified Franz diffusion cells. Heat-separated human epidermal membrane was prepared from whole skin of a human corpse using the method of Klingman and Christopher, 88, Arch. Dermatol., 702 (1963). The full thickness of the skin was exposed to heat at 60 ° C for 60 seconds, after which the stratum corneum (horny layer) and part of the epidermis (epidermal membrane) were carefully removed from the dermis (dermis). The epidermal membrane and nicotine patches were cut into 1 cm ² pieces. After removing the proximal release liner, the exposed nicotine-containing adhesive matrix was laminated to the stratum corneum surface of the epidermal membrane. The skin / adhesive matrix composite was then placed on the diffusion cell with the epidermal side facing the receiving chamber and secured in place. The receiving chamber was then filled with a pH 4.0 citrate / phosphate buffer. The cell was then placed in a circulating water bath which was calibrated to maintain the skin surface temperature at 32 ° C ± 1 ° C.

wobei C_n die Konzentration (μg/ml) des Arzneistoffs in der Aufnahmeprobe zum entsprechenden Zeitpunkt, V das Volumen der Flüssigkeit in der Aufnahmekammer (≈ 6,3 cm³) und A die Diffusionsfläche der Zelle (0,64 cm²) sind. Die Steigung der am besten passenden Gerade zur Q_t über t-Auftragung ergibt den Fluss im Fließgleichgewicht (J_ss, μg/cm²/h).After predetermined time intervals, the entire contents of the containment chamber were collected for the quantitative determination of nicotine and the containment chamber was refilled with fresh citrate / phosphate buffer, taking care to remove the air bubbles at the skin / buffer interface. The cumulative amount of drug penetrated per unit area at any time t (Q _t , μg / cm ² ) was determined according to the following equation:

where C _{n is} the concentration (μg / ml) of the drug in the receiving sample at the corresponding point in time, V the volume of the liquid in the receiving chamber (≈ 6.3 cm ³ ) and A the diffusion area of the cell (0.64 cm ² ). The slope of the best fitting straight line to the Q _t over t plot gives the flow in steady state (J _ss , μg / cm ² / h).

In vitro skin flow results from active laminates made according to Example 4 are shown in Table 2 shown. The nicotine skin flow increased linearly with the drug load, as in 5 shown. The equation of the line is y = -31.505 + 0.71447x, and the correlation coefficient is R ² = 0.987.

Example 6:

An active albuterol laminate containing a volatile booster formulation was made using the procedures described in Example 2 and using a transparent backing film (Scotchpak 1012, 3M). The amplifier consisted of a mixture of ethanol / water / glycerol monooleate / methyl laurate / launl alcohol in volume ratios of 70/1515/5/5. The free base of albuterol was dissolved in the amplifier at a final concentration of 100 mg / ml. The pH was adjusted to pH 5.5 with acetic acid and the mixture was gelled with 2% HPC (Klucel GF). The active gel was extruded between adhesive layers to create an active laminate. The active laminate was immediately punched into 5 cm ² plasters and sealed in a polyethylene-lined foil pouch. The albuterol content was determined to be 4.14 ± 0.29 mg / plaster. The in vitro skin flow, which was determined as described in Example 5, was determined to be 0.2 μg / cm ² / h.

Although the examples above and the description above describes the production of an active nicotine laminate can demonstrate that is suitable for transdermal delivery Processes used to make other active penetrants or Administer drugs through the skin or mucous membrane. Therefore the above examples are only illustrative of a complete and preferred embodiment, which when performing of the present invention can be used. The invention is aimed at discovering that the correct wording different fleeting and / or more sensitive to heat Drugs in the units for transdermal and transmucosal Delivery for administration to the stratum corneum or mucosa of a human or other animal can be formulated. Therefore can be a certain number of attempts by the specialist within of the guidelines presented here are easily carried out, to get optimal formulations. Therefore the invention is regarding the scope only by the following claims and their functional equivalents limited.

Claims (38)

A method of making a transdermal or transmucosal drug delivery device that includes a drug-containing adhesive composite layer with a distal carrier material that is impermeable to the drug and that is laminated to the distal surface of the composite layer and with a proximal peelable film which is substantially impermeable to the drug and is designed so that it can be removed to deliver the drug to the skin or mucosa, and which is laminated to the proximal surface of the composite layer, the method comprising the following steps : a) providing a first adhesive laminate comprising a first drug-permeable adhesive layer, on one surface of which the distal carrier material is laminated, the surface opposite the first adhesive layer being exposed, b) providing a z wide adhesive laminate comprising a second adhesive layer on one of which Surface of the proximal peelable film is laminated, the surface opposite the second adhesive layer being exposed, c) extruding the drug in gel form onto at least one exposed surface of the first or second adhesive laminate, and d) laminating together the exposed surfaces of the first adhesive laminate and the second adhesive laminate, at least one of which contains the extruded, gelled drug, so that the first and second adhesive layers and the gelled drug are combined to produce the drug-containing, adhesive, composite layer, the distal carrier material one surface of which covers and the proximal peelable film covers its opposite surface. The method of claim 1, wherein the extruding of the gelled drug and laminating the exposed ones together surfaces the laminate is a continuous process. The method of claim 2, wherein the extrusion and lamination steps take place substantially simultaneously. The method of claim 1, wherein the drug has a melting point of below about 100 ° C or at this Temperature is decomposed or deactivated. The method of claim 4, wherein the temperature is below about 75 ° C lies. The method of claim 1, wherein the drug Nicotine or one of its acidic addition salts. The method of claim 6, wherein the drug Nicotine base. The method of claim 1, wherein the drug is gelled by adding a small amount of a substance, the selected is from the group consisting of hydroxypropyl cellulose, hydroxymethyl cellulose, Methyl cellulose and an acrylic thickener. The method of claim 8, wherein the first and the second adhesive Layer comprising adhesive is selected from the group consisting of from acrylic resin derivatives, vinyl acetates, natural and synthetic rubber, Ethylene-vinyl acetate copolymers, polysiloxanes, polyacrylates, polyurethanes, plasticized weight of polyether block amide copolymers and their Mixtures. The method of claim 9, wherein the first and the second adhesive Layer comprising adhesives are different. The method of claim 10, wherein the drug greater permeability in which the first adhesive Layer comprising adhesive than in the second adhesive layer comprehensive adhesive, which allows the diffusion of the drug in the second adhesive Layer from the unit into the skin or mucous membrane to determine the speed becomes. The method of claim 10, wherein the drug greater permeability in which the second adhesive Layer comprising adhesive than in the first adhesive layer comprehensive adhesive, resulting in a quick release of the drug from the second adhesive Layer and prolonged release from the first adhesive Layer is reached. The method of claim 10, wherein at least one of the layers that are selected is from the group consisting of the first adhesive layer and the second adhesive Layer, a composite, adhesive layer with a proximal adhesive Layer and a distal adhesive Layer in which the proximal and distal layers Layer comprising adhesives different permeabilities for the drug have, whereby the delivery of the drug by the unit being affected. The method of claim 9, wherein the first and the second adhesive Layer comprising adhesives are the same. The method of claim 14, wherein the adhesive selected is from the group consisting of cross-linked and uncross-linked acrylic copolymers. The method of claim 9, wherein the gelled drug also contains an antioxidant. The method of claim 3, wherein the gelled drug contains a remedy that selected is from the group consisting of penetration enhancers, anti-irritants and Solvents. The method of claim 17, wherein the gelled drug a penetration amplifier contains the transport of the drug through the skin or mucous membrane facilitated. The method of claim 18, wherein the penetration enhancer is selected from the group consisting of an organic solvent and a cell envelope interfering compound and their mixtures. The method of claim 19, wherein the organic solvent is selected from the group consisting of water, diols, C ₁ -C ₃ alkanols, DMSO, dimethylformamide, N, N-dimethylacetamide, 2-pyrrolidone, N- (2-hydroxyethyl) pyrrolidone, N-methylpyrrolidone, 1-alkylazacycloheptan-2-ones and 1-anlazacycloalkyl-2-ones, and the cell envelope interfering compound is selected from the group consisting of isopropyl myristate, methyl laurate, oleic acid, oleyl alcohol, glycerol monooleate, glycerol dioleate, glycerol dioleate, glycerol diol Glycerol monostearate, glycerol monolaurate, propylene glycol monolaurate and sorbitan esters. Transdermal or transmucosal drug delivery device ( 10 ) comprising: a) a drug-containing adhesive composite layer ( 18 ) that is designed to adhere to the skin or mucous membrane that has a first distal adhesive layer ( 19 ), a second proximal adhesive layer ( 20 ) and a gelled drug layer arranged between them ( 21 ), b) a drug-impermeable distal layer on the distal surface of the adhesive, composite layer ( 18 ) laminated carrier material ( 14 ) and c) a proximal, peelable film essentially impermeable to the drug ( 22 ) on a proximal surface of the composite layer ( 18 ) is laminated, which is designed so that it can be removed to administer the drug to the skin or mucous membrane. The unit of claim 21, wherein the drug has a melting point of below about 100 ° C or at this Temperature is decomposed or deactivated. The unit of claim 22, wherein the temperature is below about 75 ° C lies. The unit of claim 21, wherein the drug Nicotine or one of its acidic addition salts. The unit of claim 24, wherein the drug Nicotine base. The unit of claim 21, wherein the drug is gelled by adding a small amount of a substance, the selected is from the group consisting of hydroxypropyl cellulose, hydroxymethyl cellulose, Methyl cellulose and an acrylic thickener. The unit of claim 26, wherein the first and second adhesive layers ( 19 . 20 ) comprehensive adhesive is selected from the group consisting of acrylic resin derivatives, vinyl acetates, natural and synthetic rubber, ethylene-vinyl acetate copolymers, polysiloxanes, polyacrylates, polyurethanes, plasticized weight of polyether block amide copolymers and mixtures thereof. The unit of claim 27, wherein the first and second adhesive layers ( 19 . 20 ) comprehensive adhesives are different. The unit of claim 28, wherein the drug has greater permeability into the first adhesive layer ( 19 ) comprising adhesive than in the second adhesive layer ( 20 ) comprising adhesive, whereby the diffusion of the drug in the second adhesive layer from the unit into the skin or mucous membrane is rate-determining. The unit of claim 28, wherein the drug has greater permeability into the second adhesive layer ( 20 ) comprising adhesive than in the first adhesive layer ( 19 ) comprehensive adhesive, which enables a rapid release of the drug from the second adhesive layer ( 20 ) and prolonged release from the first adhesive layer ( 19 ) is reached. The unit of claim 28, wherein at least one of the layers selected from the group consisting of the first adhesive layer ( 19 ) and the second adhesive layer ( 20 ), comprises a composite adhesive layer with a proximal adhesive layer and a distal adhesive layer, in which the adhesives comprising the proximal layer and the distal layer have different permeabilities for the drug, whereby the delivery of the drug is influenced by the unit. The unit of claim 27, wherein the first and second adhesive layers ( 19 . 20 ) comprehensive adhesives are the same. 33. The assembly of claim 32, wherein the adhesive is selected from the group consisting of cross-linked and uncross-linked acrylic copolymers. The unit of claim 27, wherein the gelled drug also contains an antioxidant. The unit of claim 21, wherein the gelled drug includes a remedy that selected is from the group consisting of penetration enhancers, anti-irritants and Solvents. The device of claim 35, wherein the gelled drug a penetration amplifier includes, the transport of the drug through the skin or mucous membrane facilitated. 37. The device of claim 36, wherein the penetration amplifier is selected from the group consisting of an organic solvent and a cell envelope interfering compound and their mixtures. The unit of claim 37, wherein the organic solvent is selected from the group consisting of water, diols, C ₁ -C ₃ alkanols, DMSO, dimethylformamide, N, N-dimethylacetamide, 2-pyrrolidone, N- (2-hydroxyethyl) pyrrolidone, N-methylpyrrolidone, 1-alkylazacycloheptan-2-ones and 1-arylazacycloalkyl-2-ones, and the cell envelope disrupting compound is selected from the group consisting of isopropyl myristate, methyl laurate, oleic acid, oleyl alcohol, glycerol monooleate, glycerol dioleate, glycerol dioleate, glycerol diol Glycerol monostearate, glycerol monolaurate, propylene glycol monolaurate and sorbitan esters.